Abstract The tumor microenvironment (TME) is recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escape, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of sterile inflammation and infection. We recently demonstrated that RAGE plays a unique oncogenetic role in pancreatic ductal adenocarcinoma (PDAC). We demonstrated that: 1) RAGE was highly expressed in mouse and human PDAC; 2) Global ablation of RAGE in mice prevented pancreatic cancer growth in a genetically-modified spontaneous mouse model (Pdx1-Cre;K-RasG12D/+;RAGE-/-) and a xenograft mouse model; 3) RAGE was essential for oncogenic K-Ras-mediated hypoxic signaling in PDAC development; and 4) The mechanism by which this occurs in part involves inflammatory response-associated metabolic changes, cell death-promoting limitations in autophagy, and a reduction in the accumulation of myeloid-derived suppressor cells and regulatory T cells. These exciting findings raise several important questions regarding novel role of RAGE in PDAC. We hypothesize that RAGE expression in multiple components of the TME is critical for PDAC development and therapy resistance. We will pursue the following aims. Aim 1: identify RAGE as a critical receptor of nuclear danger signal in the TME; Aim 2: define the cell-specific role of RAGE in the TME; and Aim 3: investigate antitumor efficacy of the combination of the RAGE inhibitor with chemoimmunotherapy in different tumor models in mice. The completion of these exciting studies will provide new insights into our understanding of the TME and guide future development of RAGE- based novel therapeutic strategies for PDAC patients.